Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.3.2.3 (glutathione synthetase)
 678 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gamma-Glutamyl-cysteine synthetase is inhibited by glutathione under conditions similar to those which prevail in vivo, thus strongly suggesting a physiologically significant feedback mechanism. Inhibition by glutathione, which is not allosteric, appears to involve the binding of glutathione to the glutamate site of the enzyme as well as to another enzyme site; the latter binding appears to require a sulfhydryl group since ophthalmic acid (gamma-glutamyl-alpha-aminobutyryl-glycine) is only a weak inhibitor. The finding that glutathione regulates its own synthesis by inhibiting synthesis of gamma-glutamyl-cysteine appears to explain observations on patients with 5-oxoprolinuria, who were shown to have a block in the gamma-glutamyl cycle consisting of a marked deficiency of glutathione synthetase and consequently of glutathione. These patients produce greater than normal amounts of gamma-glutamyl-cysteine, which is converted by the action of gamma-glutamyl cyclotransferase to 5-oxoproline; production of the latter compound exceeds the capacity of 5-oxoprolinase to convert it to glutamate. The apparent Km value for L-cysteine for gamma-glutamyl-cysteine synthetase (0.35 mM) is not far from intracellular concentrations of L-cysteine suggesting that the availability of L-cysteine may also play a role in the regulation of glutathione synthesis.
 ...
PMID:Regulation of gamma-glutamyl-cysteine synthetase by nonallosteric feedback inhibition by glutathione. 111 10

The primary metabolic defect in 5-oxoprolinuria (pyroglutamic aciduria) is the lack of glutathione synthetase. The mechanism of the concomitant overproduction of 5-oxoproline was studied using cell-free extracts of erythrocytes from control individuals and from patients with 5-oxoprolinuria. Such extracts catalyzed the synthesis of 5-oxoproline from L-glutamate. Addition of ATP, Mg ions and alpha-aminobutyrate was needed for optimal activity. The conversion of glutamate to 5-oxoproline occurred in two steps, catalyzed by gamma-glutamyl-cysteine synthetase and gamma-glutamyl cyclotransferase, respectively. Extracts of erythrocytes from control subjects and patients with 5-oxoprolinuria had identical capacity to synthesize 5-oxoproline. The conversion of glutamate to 5-oxoproline was markedly inhibited by reduced glutathione, which exerted its effect on the gamma-glutamyl-cysteine synthetase step. The following mechanism is postulated for the overproduction of 5-oxoproline in 5-oxoprolinuria: the deficiency of glutathione synthetase causes a lack of glutathione which is an essential feed-back inhibitor in the initial step of its biosynthesis. Therefore gamma-glutamyl-cysteine is produced in excessive amounts and it is subsequently converted to 5-oxoproline (and cysteine) by gamma-glutamyl cyclotransferase. This overproduction of 5-oxoproline exceeds the capacity of the 5-oxoprolinase and 5-oxoproline accumulates in body fluids.
 ...
PMID:On the mechanism of 5-oxoproline overproduction in 5-oxoprolinuria. 126 Oct 42

Sertoli cells play a major role in the regulation of spermatogenic cell energy metabolism and differentiation. This study demonstrates that Sertoli cells are essential for the maintenance of spermatogenic cell glutathione (GSH), an important intracellular reductant and detoxicant. Primary spermatocytes and round spermatids isolated from Xenopus laevis contained 1.5 +/- 0.1 mM GSH, but sperm lacked detectable GSH. During a 5-day culture period, isolated spermatocytes and spermatids lost 80% of the initial GSH (t 1/2 = 55 h). The levels of GSH were unaffected by L-buthionine-SR-sulfoximine (BSO), a selective inhibitor of GSH synthesis. Cultures of testicular lobules and spermatocysts (composed of germ cells and Sertoli cells) depleted of interstitial tissue lost only 30% of their initial GSH in 4.5 days; the GSH levels decreased during treatment with BSO. Spermatogenic cells in cultured testes maintained their GSH levels for 7 days by a BSO-sensitive mechanism. These results demonstrate that the intracellular GSH levels of spermatogenic cells are dependent upon germ cell-somatic cell interactions. Spermatogenic cells were shown to possess gamma-glutamyl transpeptidase, glutathione synthetase, 5-oxoprolinase, and gamma-glutamylcysteine synthetase activities. [35S] Cysteine incorporation and distribution as analyzed by high performance liquid chromatography (HPLC) showed that isolated spermatogenic cells are capable of GSH synthesis. The rate of GSH synthesis, however, was insufficient to compensate for GSH turnover. These results demonstrate that production of spermatogenic cell GSH is dependent upon Sertoli cells. To our knowledge, this is the first evidence that interactions between different cell types may be of significance in GSH metabolism.
 ...
PMID:Spermatogenic cell-somatic cell interactions are required for maintenance of spermatogenic cell glutathione. 272 29

Glutathione functions in catalysis, metabolism, transport, and reductive processes and in protection of cells by destruction of free radicals, reactive oxygen intermediates, and other toxic compounds of endogenous and exogenous origin. It also functions as a storage and transport form of cysteine. Depletion of glutathione (effectively accomplished by inhibition of its synthesis) increases sensitivity to radiation and to certain toxic compounds and is of value in combination with radiation therapy or chemotherapy in situations in which cell selectivity can be achieved. Increased cellular levels of glutathione protect cells against radiation and certain toxic compounds. Glutathione levels can be increased by administration of cysteine or of glutathione, but these approaches are not entirely satisfactory. Cellular glutathione levels can be increased by supplying substrate for gamma-glutamylcysteine synthetase or for glutathione synthetase. L-2-Oxothiazolidine-4-carboxylate is well transported into many cells and is converted by 5-oxoprolinase to cysteine, a substrate of gamma-glutamylcysteine synthetase. gamma-Glutamylcysteine and related compounds are effectively transported, especially into renal cells, thus providing substrate for glutathione synthetase; higher than normal levels of glutathione can be achieved because this enzyme is not significantly inhibited by glutathione, whereas gamma-glutamylcysteine synthetase is feedback-inhibited. Derivatives of glutathione that are effectively transported into cells (glutathione itself is not) offer another means of increasing glutathione levels. The monoethyl ester of glutathione (in which the glycine carboxyl group is esterified) is well transported in vivo into liver and kidney and into cultured fibroblasts and lymphoid cells. Glutathione levels much higher than usual can be obtained by this procedure, which protects lymphoid cells against the lethal effects of irradiation and mice against acetaminophen, and which therefore may be a relatively safe way to increase cellular resistance to radiation and certain toxic compounds.
 ...
PMID:Intracellular cysteine and glutathione delivery systems. 372 29

Enzyme studies on placenta, cultured skin fibroblasts, and erythrocytes from two sisters with the inborn error 5-oxoprolinuria (pyroglutamic aciduria) indicate that the metabolic lesion in this disease is at the glutathione synthetase (EC 6.3.2.3) step of the gamma-glutamyl cycle. Excessive urinary excretion of 5-oxoproline by these patients appears to be associated with increased synthesis of gamma-glutamyl-cysteine and formation of 5-oxoproline from this dipeptide. Thus, 5-oxoproline is produced in amounts that exceed the normal capacity of 5-oxoprolinase to convert it to glutamate. The data indicate that it may be possible to identify individuals who are heterozygous for this trait by determinations of erythrocyte glutathione synthetase.
 ...
PMID:Glutathione synthetase deficiency, an inborn error of metabolism involving the gamma-glutamyl cycle in patients with 5-oxoprolinuria (pyroglutamic aciduria). 415 48

Two brothers, aged 16 and 11 years, had recurrent episodes of vomiting, diarrhoea and abdominal pain, starting in infancy. In spite of extensive investigations no cause of their enterocolitis could be established. After several years symptomatic treatment was discontinued without any recurrence of symptoms. Their father and several paternal relatives have had kidney stones. Both boys developed urolithiasis and an oxalate-containing stone was removed from the elder brother's kidney. He had no hypercalciuria. His glomerular and tubular function tests were normal. Gas chromatography of urine from both brothers revealed massive excretion of L-5-oxoproline (pyroglutamic acid). Glutathione levels in erythrocytes of both patients were normal. The activities of enzymes of the gamma-glutamyl cycle were analysed in erythrocytes, leukocytes and cultured skin fibroblasts. The level of glutathione synthetase was normal, as was the affinity of this enzyme for its substrate gamma-glutamyl-cysteine. Feedback inhibition of gamma-glutamyl-cysteine synthetase by glutathione was also normal. Both patients had a specific deficiency of 5-oxoprolinase, the activity of which was 2-4% of that of control subjects. Their parents had intermediate 5-oxoprolinase activities in fibroblasts, indicating a recessive mode of inheritance. Thus, 5-oxoprolinuria in these two patients was due to a lack of 5-oxoprolinase, i.e., a new inborn error in the gamma-glutamyl cycle.
 ...
PMID:5-oxoprolinuria due to hereditary 5-oxoprolinase deficiency in two brothers--a new inborn error of the gamma-glutamyl cycle. 611 26

In the gamma-glutamyl cycle, hereditary defects have been described in four of the six enzymes namely: gamma-GC synthetase; GSH synthetase; gamma-glutamyl transpeptidase and 5-oxoprolinase. Mutants are still to be found in gamma-glutamyl cyclotransferase and in the dipeptidase. Deficiency of GSH synthatase or gamma-GC synthetases results in low levels of GSH. In gamma-GC synthetase deficiency hemolytic anemia is the most prominent symptom, with or without hepatosplenomegaly. In generalized GSH synthetase deficiency 5-oxoproline is overproduced due to lack of feedback inhibition of gamma-GC synthetase. These patients have metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and about 50% of them also have progressive neurological symptoms. Treatment includes acidosis correction, high doses of vitamin E and C and avoidance of drugs precipitating hemolytic crises in G6PD deficiency. Therapeutic trials with GSH analogues, N-acetylcysteine and GSH esters have been carried out. Glutathione synthetase deficiency restricted to erythrocytes results in hemolytic anemia but no 5-oxoprolinuria. gamma-Glutamyl transpeptidase deficiency is associated with GSH-emia and GSH-uria whereas 5-oxoprolinase deficiency is associated with 5-oxoprolinuria. In diagnostic work it must be emphasized that erythrocytes contain an incomplete gamma-glutamyl cycle; they lack both gamma-glutamyl transpeptidase and 5-oxoprolinase and these enzyme activities must therefore be analyzed in other types of cells such as leukocytes and fibroblasts. It is also important to investigate other patients with inherited defects in the gamma-glutamyl cycle to learn more about the biological role of GSH in man.
 ...
PMID:Patients with genetic defects in the gamma-glutamyl cycle. 967 48

Pyroglutamic aciduria (5-oxoprolinuria) is a rare autosomal recessive disorder caused by either glutathione synthetase deficiency (GSSD) or 5-oxoprolinase deficiency. GSSD results in low glutathione levels in erythrocytes and may present with hemolytic anemia alone or together with pyroglutamic aciduria, metabolic acidosis, and CNS damage. Five patients with pyroglutamic aciduria were studied. All presented with hemolytic anemia and metabolic acidosis. Two (brothers) also had Fanconi nephropathy, which is not seen in pyroglutamic aciduria. Molecular analyses of the GSS gene was performed in 3 patients. RT-PCR and heteroduplex analysis identified a homozygous deletion in 1 patient and a homozygous mutation in 2 others (brothers with Fanconi nephropathy). Sequencing of glutathione synthetase (GSS) cDNA from the first patient showed a 141-bp deletion corresponding to the entire exon 4, whilst the corresponding genomic DNA showed a G491 --> A homozygous splice site mutation. Sequencing of GSS cDNA from the Fanconi nephropathy patients showed a C847 --> T [ARG283 --> CYS] mutation in exon 9.
 ...
PMID:Clinical, biochemical, and molecular characterization of patients with glutathione synthetase deficiency. 1045 Aug 61

Pyroglutamic aciduria (5-oxoprolinuria) is a rare autosomal recessive disorder caused by either glutathione synthetase deficiency (GSSD) or 5-oxoprolinase deficiency. The severe form of the disease, generalized GSSD, is characterized by acute metabolic acidosis, usually present in the neonatal period with hemolytic anemia and progressive encephalopathy. We report a female infant who had a severe metabolic acidosis with high anion gap, hemolytic anemia, and hyperbilirubinemia. High level of 5-oxoproline was detected in her urine and a diagnosis of generalized GSSD was made. She died of severe metabolic acidosis and sepsis at the age of six weeks.
 ...
PMID:A newborn infant with generalized glutathione synthetase deficiency. 1507 78

5-Oxoprolinuria is primarily associated with inborn errors of the gamma-glutamyl cycle. In addition, transient 5-oxoprolinuria has been reported to occur in a variety of conditions, such as prematurity and malnutrition, and during medication. We report an unusual case of permanent 5-oxoprolinuria. The patient presented 3 days after birth with acidosis, and metabolic screening revealed massive excretion of 5-oxoproline. Following recovery, growth and psychomotor development were normal, but 5-oxoprolinuria persisted. Primary defects in the gamma-glutamyl cycle were ruled out since glutathione synthase and 5-oxoprolinase activities were normal. All known secondary causes of 5-oxoprolinuria were also excluded, leaving the basis of the permanent 5-oxoprolinuria in this patient unresolved.
 ...
PMID:Persistent 5-oxoprolinuria with normal glutathione synthase and 5-oxoprolinase activities. 1683 Feb 60


1 2 Next >>